The overarching goal of this project is to identify the defining characteristics of disease neurons in Anorexia Nervosa (AN), in the course of addressing the interplay between risk conferring genetic variations, excess of dopamine receptors, inability to sense reward and the extreme food restricting phenotype of AN. Anorexia nervosa is a highly heritable disorder with the highest mortality among psychiatric illnesses, yet lacking effective treatments. Highly malnourished status at death has obstructed the study of brain tissue for mechanistic clues. Genetic reprogramming of somatic cells to a pluripotent state produces induced pluripotent stem cells (iPSCs), and has been accomplished using human cells. The resulting iPSCs are isogenic to the donor individual, i.e., they carry a similar genetic background, and can be differentiated into functional neurons. Thus, iPSCs are extremely attractive for understanding complex neuropsychiatric diseases such as AN, where accessing and analyzing neural tissue is a tremendous rate-limiting step. The special value of using human iPSCs as a biological tool to understand untreatable brain disorders such as AN, comes not only from the promise of insights into brain pathophysiology, but also for the potential to accelerate the discovery of therapeutics that can modify progression of this adolescent-onset illness. Not surprisingly, the remarkable potential of iPSCs has sparked profuse interest and excitement in researchers studying individuals with a variety of neuropsychiatric disorders, because of their potential to reveal avenues for intervention. The study of AN in this collaborative proposal provides an ideal setting as we will leverage a locally collected cohort of adolescents with AN and their families via the International AN Treatment Study, who are being assessed by our group for clinical course, treatment outcome, genetic sequencing (Price Foundation grant) and neuroimaging of the reward pathway. Thus, this proposal maximizes the potential scientific impact of a combination of innovative technologies while remarkably enhancing their feasibility. Furthermore, the extreme clinical phenotype of AN combined with emerging data on risk conferring genes and deficits in sensing reward make a compelling case for the proposed study. To this end, the Specific Aims are: (1) to derive iPSCs from individuals with AN as well as healthy controls; (2) to analyze the gene expression profile of neural cells derived from controls and AN iPSCs; and (3) to test cross-level hypotheses, e.g., the neural mechanisms that result in the excess of dopamine receptors seen via neuroimaging and to determine the contribution of risk conferring genetic mechanisms to this process. The pluripotent stem cells will be driven to differentiate into dopaminergic neurons for future mechanistic explorations based on our hypotheses. Elucidating the links between genes, reward mechanisms and extremes of eating behaviors have the unmistakable potential of yielding mechanistic and therapeutic knowledge of not only anorexia nervosa but also of the emerging epidemic of obesity.